Methods of treating pulmonary diseases and disorders

Abstract

The present disclosure features disclosed method of treating disorders such as COPD, bronchitis and/or asthma using disclosed compounds, optionally together with one or more additional active agents. Contemplated methods include administrating orally or by inhalation to a patient one or more disclosed compounds.

What is claimed is: 
     
         1 . A method of treating chronic obstructive pulmonary disease, bronchitis, or asthma in a patient in need thereof, or in a patient at risk of developing chronic obstructive pulmonary disease, comprising a) administering an effective amount of a compound represented by Formula A and b) optionally administering an effective amount of one or more of an additional active agent, wherein Formula A is: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, wherein:
 R 22  is optional, and is selected, independently, for each occurrence if present from the group consisting of halogen, and C 1-4 alkyl (optionally substituted by one, two or three halogens); 
 pp is 0, 1, 2 or 3; 
 R 31  is selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl; 
 L 1  is selected from the group consisting of C 3-9  cycloalkylene, C 1 alkylene-C 3-9  cycloalkylene- and —C 3-9  cycloalkylene-C 1 alkylene, wherein L 1  may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C 1-3 alkyl (optionally substituted by one, two or three substituents each selected independently from R ff ); 
 R 44  is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl, 4 to 6 membered heterocycloalkyl, C 1-3 alkyl, and —C(O)—OR′, wherein the heteroaryl has one, two or three heteroatoms each selected from O, N, and S; and wherein the heteroaryl or heterocycloalkyl may be optionally substituted by one or two substituents each selected independently from R gg ; 
 R ff  is selected for each occurrence from group consisting of halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkyoxy, C 2-4 alkenyl, oxo, —NR′R″, —NR′—S(O) w —C 1-3 alkyl, S(O) w —NR′R″, and —S(O) w —C 1-3 alkyl, where w is 0, 1, or 2, wherein C 1-4 alkyl, C 1-4 alkyoxy, and C 2-4 alkenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, —NR′R″, —NR′—S(O) w —C 1-3 alkyl, S(O) w —NR′R″, and —S(O) w —C 1-3 alkyl; 
 R gg  is selected for each occurrence from group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, —O—C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —C(O)—O-phenyl, —O—C(O)-phenyl, phenyl, 4 to 6 membered heterocycloalkyl, —NR′R″, oxo, —NR′—S(O) w —C 1-3 alkyl, S(O) w —NR′R″, and —S(O) w —C 1-3 alkyl, where w is 0, 1, or 2, wherein C 1-6 alkyl, C 1-6 alkyoxy, C 2-6 alkenyl C 3-6 cycloalkyl, phenyl and heterocycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, C(O)OH, —C(O)OC 1-6 alkyl, —O—C(O)C 1-6 alkyl, O—C(O)-phenyl, —C(O)O—NR′—C 1-6 alkyl, —O—C 3-6 cycloalkyl, —O-heterocycle, phenyl, —O— heteroaryl, —O-phenyl, —NR′R″, —NR′—S(O) w —C 1-3 alkyl, S(O)w-NR′R″, and —S(O) w —C 1-3 alkyl, where w is 0, 1, or 2; and 
 R′ and R″ are each independently selected for each occurrence from H and C 1-4 alkyl or taken together with the nitrogen to which they are attached form a heterocyclic ring. 
 
     
     
         2 . The method of  claim 1 , wherein the chronic obstructive pulmonary disease is emphysema. 
     
     
         3 . The method of  claim 1  or  2 , wherein the additional active agent is selected from the group consisting of: β 2  agonists, muscarinic antagonists, anticholinergics, corticosteroids, methylxanthine compounds, antihistamines, decongestants, anti-tussive drug substances, PDE I-VI inhibitors, prostacycline analogs, mucolytics, calcium blockers and CFTR modulators. 
     
     
         4 . The method of  claim 3 , wherein the corticosteroid is selected from the group consisting of: dexamethasone, budesonide, beclomethasone, triamcinolone, dexamethasone, mometasone, ciclesonide, fluticasone, flunisolide, dexamethasone sodium phosphate and pharmaceutically acceptable salts and esters thereof. 
     
     
         5 . The method of any one of  claims 1 - 3 , wherein the additional active agent is selected from the group consisting of interferon γ1β; bosentan, entanercept, and imatinib mesylate. 
     
     
         6 . The method of  claim 3 , wherein the β-agonist is a long acting β-agonist. 
     
     
         7 . The method of  claim 3 , wherein the β-agonist is selected from the group consisting of: albuterol, formoterol, pirbuterol, metapoterenol, salmeterol, arformoterol, indacaterol, levalbuterol, terbutaline and pharmaceutically acceptable salts thereof. 
     
     
         8 . The method of  claim 3 , wherein the corticosteroid is selected from budesonide or beclomethasone dipropionate. 
     
     
         9 . The method of any one of  claims 1 - 3 , wherein at least two additional active agents are administered and are each selected from the group consisting of vilanterol, umeclidine, formoterol, salmeterol, budesone, fluticasone and pharmaceutically acceptable salts thereof. 
     
     
         10 . The method of  claims 1 - 3 , wherein the at least one additional active agent is a long acting muscarinic antagonist selected from the group consisting of tiotropium, glycopyrronium, aclidinium and pharmaceutically acceptable salts thereof. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein at least two additional active agents are administered. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein at least one additional active agent is a CFTR corrector or potentiator. 
     
     
         13 . The method of any one of  claims 1 - 12  wherein the risk factor for developing chronic obstructive pulmonary disorder in a patient is a history of smoking or having mesothelioma. 
     
     
         14 . The method of any one of  claims 1 - 12 , wherein the risk factor for developing chronic obstructive pulmonary disorder is air pollution. 
     
     
         15 . The method of any one of  claims 1 - 9 , wherein administering an effective amount of a compound represented by Formula A is orally or by inhalation. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein administering an effective amount of additional active agent is oral or inhalation administration. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein R 22  is selected independently for each occurrence from H and F. 
     
     
         18 . The method of any one of  claims 1 - 16 , wherein pp is 0 or 1. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein L 1  is C 3-6  cycloalkylene. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein L 1  is selected from the group consisting of C 3 cycloalkylene, —C 4 cycloalkylene-, C 5 cycloalkylene, C 6 cycloalkylene, -bicyclo[1.1.1]pentane-, -bicyclo[2.2.1]heptane-, and bicyclo[3.2.1]octane-. 
     
     
         21 . The method of any one of  claims 1 - 20 , wherein L 1  is selected from the group consisting of —C 1 alkylene-C 4 cycloalkylene, C 4 cycloalkylene, and C 4 cycloalkylene-C 1 alkylene-. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein L 1  is C 4 cycloalkylene. 
     
     
         23 . The method of  claims 1 - 22 , wherein L 1  is substituted by one or two substituents each selected from the group consisting of halogen, hydroxyl, and C 1-3 alkyl. 
     
     
         24 . The method of any one of  claims 1 - 22 , wherein R 44  is a 5-6 membered monocyclic heteroaryl, optionally substituted by one or two substituents each selected independently from R gg . 
     
     
         25 . The method of any one of  claims 1 - 22 , wherein R 44  is a 9-10 membered bicyclic heteroaryl, optionally substituted by one or two substituents each selected independently from R gg . 
     
     
         26 . The method of any one of  claims 1 - 22 , wherein R 44  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein X 2  independently for each occurrence is selected from the group consisting of O or S; each R 66 , R 77  and R 88  is independently selected for each occurrence from H and R gg . 
       
     
     
         27 . The method of  claim 26 , wherein R 44  is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 26  or  27 , wherein R 66 , R 77  and R 88  are each independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, and heterocycloalkyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, and heterocycloalkyl are optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —S(O) w —C 1-3 alkyl (w is 0, 1, or 2) and —NR′S(O) 2 C 1-6 alkyl; and
 R′ and R″ are each independently selected for each occurrence from H and C 1-4 alkyl. 
 
     
     
         29 . The method of any one of  claims 26 - 29 , wherein R 66 , R 77  and R 88  are each independently selected from the group selected from C 1-4 alkyl, optionally substituted by one or two hydroxyls. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein R 44  is heterocycloalkyl. 
     
     
         31 . The method of  claim 30 , wherein R 44  is 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of any one of  claims 1 - 31 , where the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of any one of  claims 1 - 32 , wherein R 44  is a 5-membered heteroaryl having two or three nitrogens. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein R 44  is a 5 membered heteroaryl having three nitrogens. 
     
     
         35 . The method of any one of  claims 1 - 34 , wherein R 44  is a 5 membered heteroaryl having two nitrogens and additional heteroatom selected from O or S. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein R 44  is substituted on a free carbon by a substituent selected from the group consisting of: a methyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, ethyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, propyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, isopropyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, n-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, t-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, s-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy and isobutyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy. 
     
     
         37 . The method of any one of  claims 27 - 29 , wherein R 44  is represented by: 
       
         
           
           
               
               
           
         
         wherein X 2  independently for each occurrence is selected from the group consisting of O or S; and R 66  is selected from the group consisting of: a methyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, ethyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, propyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, isopropyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, n-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, t-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, s-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, and isobutyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy. 
       
     
     
         38 . The method of  claims 34 - 37 , wherein R 44  is represented by: 
       
         
           
           
               
               
           
         
         wherein R 77  and R 88  are each independently selected from the group consisting of: hydrogen, a methyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, ethyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, propyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, isopropyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, n-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, t-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, s-butyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy, and isobutyl substituted by one, two or three substituents each selected from halogen, hydroxyl, methoxy and ethoxy. 
       
     
     
         39 . The method of 38 or 37, wherein R 66 , R 77  or R 88  is a selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R ggg  is selected from the group consisting of H, C 1-6 alkyl, C(O)OH, —C(O)OC 1-6 alkyl, C(O)O-phenyl, and phenyl. 
       
     
     
         40 . The method of  claim 1 , wherein the compound of formula A is selected from the group consisting of: N-trans-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(4-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-((trans-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl)-5-phenylisoxazole-3-carboxamide; N-((cis-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl)-5-phenylisoxazole-3-carboxamide; N-((trans-3-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-((cis-3-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(4-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(4-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-(5-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-(4-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-((R)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylioxazole-3-carboxamide; N-cis-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(5-((R)-1,2-dihydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; (1-cis-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1H-1,2,3-triazol-4-yl)methyl butylcarbamate; N-trans-3-(4-(R)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(4-(S)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(5-((R)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(5-((S)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-trans-3-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-((5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-((5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; 5-phenyl-N-[(trans-3-([5-[(1R)-1-hydroxyethyl]-1,3,4-thiadiazol-2-yl]methyl)cyclobutyl]isoxazole-3-carboxamide; 5-phenyl-N-[(cis-3-([5-[(1R)-1-hydroxyethyl]-1,3,4-thiadiazol-2-yl]methyl)cyclobutyl]isoxazole-3-carboxamide; N-trans-3-(2-hydroxyethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-cis-3-(2-hydroxyethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-(methylsulfonamidomethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(3-((S)-1-hydroxyethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(3-((R)-1-hydroxyethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(cis-3-((5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-((5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-((trans-3-((5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-((cis-3-((5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((R)-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((S)-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; 5-phenyl-N-[trans-3-[5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide; 5-(4-fluorophenyl)-N-[trans-3-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide; 5-phenyl-N-[trans-3-[5-[(1R)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide; (1R)-1-[5-[trans-3-(5-phenylisoxazole-3-amido)cyclobutyl]-1,3,4-oxadiazol-2-yl]ethyl acetate; (R)-1-(5-(trans-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1,3,4-oxadiazol-2-yl)ethyl benzoate; N-(trans-3-(5-((R)-1-isopropoxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-((R)-1-isobutoxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; tert-butyl 3-(5-(trans-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate; 5-phenyl-N-[trans-3-[5-(azetidin-3-yl)-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide; N-(trans-3-(5-(oxetan-3-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; 5-(2,4-difluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; 5-(3-fluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; 5-(2-fluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; 5-(4-hydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; 5-(3-hydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; 5-(3,4-difluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; N-(trans-3-(5-((R)-1-(methylsulfonyl)ethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-cyclobutyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(1H-imidazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide; N-(3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide; N-(3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide; N-[3-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]cyclopentyl]-5-phenylisoxazole-3-carboxamide; N-(cis/trans-4-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide; 5-(3,4-dihydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide; N-(trans-3-(1H-benzo[d]imidazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(trans-3-(5-(1,1-dioxidothietan-3-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide; N-(3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-5-phenylisoxazole-3-carboxamide; and N-(3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-5-phenylisoxazole-3-carboxamide, and pharmaceutically acceptable salts thereof.